Treatment method against side-effects of chemotherapy

ABSTRACT

A method and composition is provided for organ rescue wherein a specific counter-measure is applied locally to a tissue at risk for or exhibiting an adverse side effect of a cancer treatment. More particularly, the method and composition is directed at controlling Hand-Foot Syndrome, a painful redness and cracking of the skin of the hands and feet which can occur with systemic treatment with 5-fluorouracil or a precursor thereof. Uracil ointment is applied to the skin of the hands and feet to prevent Hand-Foot Syndrome which can occur from systemic administration of 5-fluorouracil (or precursor thereof) as cancer treatment.

CROSS-REFERENCES

This application is a continuation-in-part application of Ser. No.10/364,383 filed Feb. 12, 2003, and which claims benefit fromProvisional Application Ser. No. 60/355,764, filed Feb. 12, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention concerns reducing side-effects of certain chemotherapy,and particularly, side-effects manifested topically in areas of thehands and feet.

2. The Related Art

Chemotherapy can result in predictable toxicity to organs. An importantchemotherapy is the use of 5-fluorouracil (5FU), and its precursors,such as capecitabine available as Xeloda®, a drug produced by RochePharmaceuticals. Xeloda® and 5FU can induce a skin side effect called“Hand-Foot Syndrome” (HFS). This syndrome can cause pain, a loss offeeling (numbness), a tingling feeling, swelling and redness in thepalms of your hands and/or soles of feet. Some patients also get a rash,discolored skin, nail problems, and hair loss. Severe cases of HFS canbe very painful, cause skin of the hands and feet to blister and peel.

Compilations relevant to this field include the following.

Mackean M, Planting A, Twelves C et al: Phase 1 and pharmacologic studyof intermittent twice-daily oral therapy with capecitabine in patientswith advanced and/or metastatic cancer. J. Clin Oncol 16:2977-2985,1998.

Cao S, Frank C, Shirasaka et al: 5-fluorouracil pro drug: role ofanabolic and catabolic pathway modulation in therapy of colorectalcancer. Clin Can Res 1:839-845, 1995.

Hoff, P: The tegafur-based dehydropyrimidine dehydrogenase inhibitoryfluoropyrimidines, UFT/Leucoverin (Orzel) and S-1: a review of theirclinical development and therapeutic potential. Invest New Drugs18:331-342, 2000.

Johnson M, Hageboutros A, Wang K, et al: Life threatening toxicity in adihydropyrimidine dehydrogenase-deficient patient after treatment withtopical 5-fluorouracil. Clin Can Res 5:2006-2011, 1999.

SUMMARY OF THE INVENTION

The present invention introduces the concept of “organ rescue.” Byapplying locally a uracil ointment, certain adverse side effects of 5FUand its precursors can be averted. Uracil and 5FU are anabolized by thesame enzymes. Uracil and 5FU differ chemically only in the H (Uracil) orF(5FU) at 5 position. Uracil is in high concentration when the uracilointment is applied at the skin subject to HFS (“rescuing” the skin).After topical application of the uracil ointment to the hands and feet,uracil has negligible concentration in the body generally andspecifically in the tumor containing regions of the body. Theapplication of 1% uracil ointment prevents the anabolism of 5FU into atoxic form in those tissues, subjacent to the ointment application,where uracil concentration is high. Adverse side effects of 5FU arecountered while preserving the anti-cancer systemic efficacy of the 5FU.With application of the uracil ointment to the hands and feet, thesystemic uracil concentration is low. No longer is it necessary toreduce the systemic dose of 5FU/precursor in efforts to avoid the HFSside-effect.

The concept of “organ rescue” can be applied to other organs and toother chemotherapy agents which have specific organ toxicities. In eachcase, the rescue agent is directly applied in high local concentrationto a tissue subject to toxicity thereby reversing the unwanted sideeffect of systematically administered anti-cancer agent. The rescueagent must, in each case, specifically reverse the local efficacy of thecancer treatment. The rescue agent must have negligible systemicconcentration in the body to preserve the anti-cancer efficacy of thecancer treatment.

Previous work presumed the oral administration of uracil, systemicallytogether with a precursor of 5FU would increase the metabolism of the5FU and decrease its degradation. The resultant effect was presumed tobe an increase in toxicity. This oral agent (UFT) is administeredsystematically at a dose of 1000-2000 mg uracil (4× molar excess over5FU) per day. It is possible that the high uracil dose in UFT cancounteract the anti-cancer effect of the 5FU. The 1% uracil ointment isadministered at 1-2 cc or 10-20 mg uracil per day.

This logic for creating mixtures of uracil and 5FU/precursor was thatthe uracil compared to 5FU would be preferentially degraded andmetabolized. Thus, the application of a 1% uracil ointment might beexpected to increase HFS. Yet, quite the opposite was observed. The 1%uracil ointment eliminated the HFS toxicity of cancer treatment by 5FUor its precursor.

DETAILED DESCRIPTION OF THE INVENTION

Use of uracil formulations can be effective as post-chemotherapytreatment providing benefit to the adverse skin effects of thechemotherapy chemicals. Among those effects that can be mitigatedinclude redness (erythema) and cracking.

Chemotherapy agents applicable to the present treatment and methodinclude 5-fluorouracil or precursors thereof

Amounts of uracil as the rescue active in rescue formulations may rangefrom about 0.01 to about 60%, preferably from about 0.5 to about 5%,optimally from about 1% by weight.

Formulations of uracil may be in any convenient format. These includecreams, lotions, aerosol sprays, roll-on liquids, sticks and pad forms.

Treatment compositions of the present invention may be anhydrous oremulsions. Oil and water emulsions are preferred for the presentinvention. Whether anhydrous or emulsion type, compositions of thepresent invention may further include a variety of pharmaceuticallyacceptable carriers and skin actives. Amounts of the carrier may rangefrom about 1 to about 99%, preferably from about 5 to about 70%,optimally from about 10 to about 40% by weight. Among the carriers areemollients, water, inorganic powders, foaming agents, emulsifiers, fattyalcohols, fatty acids, and combinations thereof

Emollients are substances selected from polyols, esters andhydrocarbons. Polyols suitable for the invention may include propyleneglycol, dipropylene glycol, polypropylene glycol, polyethylene glycol,sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol,1,2,6-hexanetriol, glycerin, ethoxylated glycerin, propoxylatedglycerin, xylitol and mixtures thereof.

Esters useful as emollients include:

(1) Alkyl esters of fatty acids having 10 to 20 carbon atoms. Methyl,isopropyl, and butyl esters of fatty acids are useful herein. Examplesinclude hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropylpalmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decylstearate, isopropyl isostearate, diisopropyl adipate, diisohexyladipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate,myristyl lactate, and cetyl lactate. Particularly preferred are C12-C15alcohol benzoate esters.

(2) Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examplesthereof include oleyl myristate, oleyl stearate and oleyl oleate.

(3) Ether-esters such as fatty acids esters of ethoxylated fattyalcohols.

(4) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty acidesters, diethylene glycol mono- and di-fatty acid esters, polyethyleneglycol (200-6000) mono- and di-fatty acid esters, polyglycerolpoly-fatty esters, ethoxylated glyceryl monostearate, 1,3-butyleneglycol monostearate, 1,3-butylene glycol distearate, polyoxyethylenepolyol fatty acid ester, sorbitan fatty acid esters, and polyoxyethylenesorbitan fatty acid esters are satisfactory polyhydric alcohol esters.

(5) Wax esters such as beeswax, spermaceti, myristyl myristate, stearylstearate.

(6) Sterol esters, of which cholesterol fatty acid esters are examplesthereof

Illustrative hydrocarbons are mineral oil, polyalphaolefins, petrolatum,isoparaffin, polybutenes and mixtures thereof.

Inorganic powders are useful carriers. Examples include clays (such asMontmorillonite, Hectorite, Laponite and Bentonite), talc, mica, silica,alumina, zeolites, sodium sulfate, sodium bicarbonate, sodium carbonate,calcium sulfate and mixtures thereof.

Aerosol propellants may also be used as carriers. Propellants arenormally based on volatile hydrocarbons such as propane, butane,isobutene, pentane, isopropane and mixtures thereof Philipps PetroleumCompany is a source of such propellants under trademarks including A31,A32, A51 and A70. Halocarbons including fluorocarbons and dimethyl etherare further widely employed propellants.

Emulsifiers may constitute at least a portion of the carrier forcompositions according to the present invention. These may be selectedfrom nonionic, anionic, cationic, or amphoteric emulsifying agents. Theymay range in amount anywhere from about 0.1 to about 20% by weight.Illustrative nonionic emulsifiers are alkoxylated compounds based onC10-C22 fatty alcohols and acids and sorbitan. These materials areavailable, for instance, from the Shell Chemical Company under theNeodol trademark. Copolymers of polyoxypropylenepolyoxyethylene sold bythe BASF Corporation under the Pluronic trademark are sometimes alsouseful. Alkyl polyglycosides available from the Henkel Corporation mayalso be utilized for purposes of this invention.

Anionic type emulsifiers include fatty acid soaps, sodium laurylsulphate, sodium lauryl ether sulphate, alkyl benzene sulphonate, mono-and di-alkyl acid phosphates, sarcosinates, taurates and sodium fattyacyl isethionate.

Amphoteric emulsifiers include such materials as dialkylamine oxide andvarious types of betaines (such as cocamidopropyl betaine).

Preservatives such as methyl paraben and propyl paraben are useful toprevent microbial contamination.

Another system for delivering uracil and similar rescue agents may bemicrosphere technology. Typical of this technology is use of a highsurface area polymethacrylate impregnated with the rescue agent.

Except in the operating and comparative examples, or where otherwiseexplicitly indicated, all numbers in this description indicating amountsof material ought to be understood as modified by the word “about.”

The following examples will more fully illustrate the embodiments ofthis invention. All parts, percentages and proportions referred toherein and in the appended claims are by weight unless otherwiseillustrated.

All documents mentioned in this application should be considered asbeing incorporated herein by reference.

EXAMPLE 1

A patient being treated with orally administered Xeloda had todiscontinue the routine after only 5 of 14 days of planned treatment.Discontinuance was the result of severe Hand-Foot Syndrome. Tumormeasurements on the original date and after 21 days subsequent toHand-Foot Syndrome recovery are recorded in Table 1 below as “initial”and “Day 21,” respectively. After two courses of treatment with Xeloda®and a concurrent topical application of 1% uracil ointment based on avanishing cream base (applied four times a day to the hands and feet),the patient had no symptoms of the syndrome. See “Day 35.” TABLE 1Original Day Day Tumor Date 21 35 Breast mass 7 × 7 cm 9 × 9 cm 8.5 ×8.5 cm Left supraclavicular 1 × 1 cm 2 × 2 cm 1.5 × 1.5 cm node Rightaxillary mass 2 × 2 cm 3 × 3 cm 2 × 2 cm

The administration of the uracil ointment both prevented the Hand-FootSyndrome as well as restored the anti-tumor activity of the Xeloda®.

This 48 year old female patient exhibited metastatic breast cancer. Shehad refused mastectomy and had previously failed adriamycin and cytoxan,weekly taxol, weekly navelbine. She was then placed on Xeloda® togetherwith 1% uracil ointment applied to the hands and feet. The 1% uracilointment was used starting with cycle 5 of treatment with Xeloda®. Table2 below summarizes results on this patient. TABLE 2 Course q3 wk 1 2 3 45 6 7 8 Xeloda dose 1250 same D/C 1000 1250 same same same 14/21 daysmg/m2 after mg/m2 mg/m2 bid × 14 4 days bid × 14 bid × 14 Taxotere 75mg/m2 + + + + + + + + Marker tumor size 12 × 12 8 × 8 7 × 7 7 × 7 9 × 98.5 × 8.5 8 × 8 8.5 × 8.5 cm-prior to rx progression on lower doseXeloda 1% uracil ointment 0 0 0 0 + + + + Hand-foot syndrome ND* ND ++++++ 0 0 0 0*Not described

The 1% uracil ointment allowed a reescalation of the dose of Xeloda® Theresults show recovered anti-tumor activity at the higher dose ofXeloda®. The 1% uracil ointment did not interfere with the anti-canceractivity of the Xeloda®. Neither did the 1% uracil ointment have anydiscernible toxicity.

EXAMPLE 2

Another patient, a 68 year old white female diagnosed with metastaticcolon cancer, was treated with Xeloda® and thalidomide. Hand-FootSyndrome developed. Complete reversal of the syndrome occurred aftertopical treatment with a 1% uracil ointment. The efficacy of the Xeloda®and thalidomide treatment was unaffected by the concurrent use if the 1%uracil ointment. There were no dose reductions of chemotherapy ortreatment delays.

EXAMPLE 3

A 60 year old white female with metastatic colon cancer was treated with5FU, Leucovocin®, and Oxaliplatin, a very common regime of treatment forthis form of cancer. The patient developed hand-foot syndrome. Topicalapplication of 1% uracil ointment resulted in complete resolution of thesyndrome. The anti-cancer treatment remained efficacious. Noside-effects were noted as a result of the uracil ointment applications.There were no dose reductions of chemotherapy or treatment delays.

The foregoing description and examples illustrate selected embodimentsof the present invention. In light thereof, variations and modificationswill be suggested to one skilled in the art, all of which are within thespirit and purview of this invention.

1. A method for organ rescue from toxicity of chemotherapeutictreatment, the method comprising topically applying a rescue agentcomposition to an area of the body at risk of or exhibiting adverse sideeffects from the cancer treatment, the rescue agent operative to reversethe efficacy of the cancer treatment due to its high local concentrationin the tissues to be rescued; the rescue agent being present in anegligible amount that systematically allows the chemotherapeutictreatment to attack cancer in an unabated manner.
 2. A method for organrescue from toxicity of cancer treatment, the method comprisingtopically applying a composition comprising a rescue agent to an area ofa human body at risk of or exhibiting adverse side effects from thecancer treatment.
 3. A method according to claim 2 wherein the adverseside effects include Hand-Foot Syndrome.
 4. A method according to claim2 wherein the side effects are conditions selected from pain, numbness,tingling feeling, swelling, redness and combinations thereof in palms ofa cancer patient's hands or soles of a cancer patient's feet.
 5. Amethod according to claim 2 wherein the cancer treatment applies ananti-cancer active which is 5-fluorouracil or a precursor thereof.
 6. Amethod according to claim 2 wherein the rescue agent is uracil.
 7. Amethod according to claim 6 wherein the rescue agent is delivered in apharmaceutically acceptable carrier selected from the group comprisingemollients, water, inorganic powders, foaming agents, emulsifiers,microspheres, and combinations thereof.
 8. A method for reducingHand-Foot Syndrome (HFS) resulting from a chemotherapeutic treatmentthrough systemic treatment with 5-fluorouracil or a precursor thereof,the method comprising topically applying to a body surface affected byHFS or at risk of HFS, a composition comprising uracil in an effectiveamount to reduce the Hand-Foot Syndrome.
 9. A composition for treatingHand-Foot Syndrome comprising about 0.01 to about 60% by weight ofuracil in a pharmaceutically acceptable carrier.
 10. A compositionaccording to claim 9 wherein the uracil is present in an amount fromabout 0.5 to about 5% by weight in a pharmaceutically acceptablecarrier.
 11. A method of reducing stomititis due to 5FU or a 5FUprecursor by applying a topical uracil composition to the oral/rectalmucosa.